2-thenylamines



Patented Dec. 12, 1950 Z-THENYLAMINES Howard D. Hartough, Pitman, and Seymour L.

Meisel, Woodbury, N. .l., assignors to Socony- Vacuum Oil Company, Incorporated, a corporation of New York No Drawing. Application July 1, 1948, Serial .No. 36,448

14 Claims. 1

The present invention relates to the preparation of C-substituted methylamines and, more particularly, to the preparation of 2-thenylamine in improved yields.

While the preparation of thenylamines and, particularly, of 2-thenylamine has been described in copending applications for United States Letters Patent Serial Nos. 636,511, filed December 21, 1945, in the names of Howard D. Hartough and Sigmund J. Lukasiewicz; 725,160, filed January 29, 1947, in the names of Howard D. Hartough and Sigmund J. Lukasiewicz, now Patent 2,497,067; and 740,194, filed April 9, 1947, in the names of Howard D. Hartough and Sigmund J Lukasiewicz, now Patent 2,492,294, it has now been discovered that C-substituted methylamines and, particularly, Z-thenylamines can be prepared in far better yields than heretofore. Thenovel process of preparing C-substituted methylamine includes preparation of the corresponding formaldimines and alcoholysis of the formaldimines.

The C-substituted methylamines are those compounds, including Z-thenylamine, which may be considered as substituted methylamines in which a hydrogen atom attached to the carbon of the methyl group is replaced by the residue of a compound having a hydrogen atom of pronounced reactivity and capable of participating in the Mannich reaction. This may be readily comprehended by consideration of the following:

Methylamine is represented by the formula CH3NH2 and dimethylamine by the formula, (CH3) 2NH. The novel compounds are represented by the generic formulae RCHzNHzand (RCHz) zNI-I where R, is the residue of a compound having a hydrogen atom of pronounced reactivity and capable of participating in the Mannich reaction. The compounds having a hydrogen atom of pronounced reactivity and capable of participating in the Mannich reaction include thiophene, furan, pyrrole, ketones, such as acetone, methylethyl ketone, 'cyclohexan-one, and malonic acids such as benzylmalonic acid, and the like.

The reaction may be said to be represented by the following equations:

RH onto NH4C1 RCH}l I=CH HCl R-omrnom ZROH RCH NHqHCl oHi oR g where H is a hydrogen atom of pronounced reactivity and R is the residue of a compound having the hydrogen atom of pronounced reactivity.

The Z-thenylamines are those compounds, in-.

cluding z-thenylamine,

I I H EL LtL-Nlh s i which may be considered as substituted Z-theny'lamines and correspond to the generic formula and substituted N-(Z-thenyl) formaldimines have a composition corresponding to R R L where R R and R. have the same significance asherein'before. The preparation of N-(2-thenyDformaIdimines has been described in the copending application for United States Letters Patent Serial No. 782,961, filed October 29, 1947, in the name of Howard D. I-Iartough. The preparation of N-(Z-thenyDfOrmaIdimine, N-(5- methyl-'2-thenyl)formaldimine and N-(tertiarybuty'l-Z-thenyl)'formaldimine is specifically described therein.

The present invention is based upon the discovery that forma'ldimines hydrolyze in aqueous acid solution in the presence of alcohols to yield amines in accordance with the following equations:

Similarly N -thenylformaldimines hydrolyze in accordance with the f ollowing equations:

N-thenylamine S lk In addition to the dithenylamine and thenylamine higher amines are also obtained.

There seems to be no specificity attached to the particular alcohol used. In fact, the alcohol may be monohydric or polyhydric. The only limitation upon the alcohol is one related to practical considerations, to wit: that the unreacted alcohol be readily removed from the reaction mixture and that the formal likewise be readily separated from the desired products. For these reasons it is preferred to use the lower monohydric alcohols such as methanol. Methanol has a lower boiling point than thiophene,

64.7" C. as compared with 84 C. for thiophene and the dimethyl formal has a low boiling point of 42.5 C. However, when higher boiling derivatives of thiophene are used correspondingly higher boiling monoor polyhydric alcohols can be used if desired. In general, it is preferred to use monoor polyhydric alcohols having boiling points not greater than about 150 C.

The N-thenylamines may be prepared from the corresponding formalcimines after isolation of the latter from the reaction mixture or the thenylamines may be prepared in situ. The latter is the preferred method.

The preparation of formaldimines has been described in copending application for United States Letters Patent Serial No. 782,962. This method involves mixing an ammonium salt such as the halide, formaldehyde and a compound having at least one hydrogen atom of pronounced reactivity, heating the resultant mixture toinitiate the reaction, thereafter cooling the mixture to ambient temperatures and recovering the formaldimine. The formaldimine is then hydro lyzed in the presence of an alcohol. The reaction can be represented by the following equation in which R represents a compound having at least one hydrogen atom of pronounced reactivity ca pable of undergoing the Mannich reaction.

EXAMPLE I About 12.5 parts by weight of N-(Z-theny iormaldimine (about 0.1 mole) was dissolved in about 150 parts by volume of methanol. About 10 parts (about Olmole) by volume of concentrated aqueous hydrochloric acid were added and the reaction mixture refluxed through a 12 -plate fractionating column. A temperature of l5-47 C. was attained in the column (pure methylal boils at 42.3 C.). The methylal was collected and a 2,4-dinitrophenylhydrazone of formaldehyde, melting point 165 C., was prepared from the methylal by standard procedures. Since no formaldehyde per se was present in the 4 reaction mixture it follows that the methylal was produced from the Iormaldimine.

EXAMPLE II About 4 moles of thiophene and about 4 moles of ammonium chloride were mixed and about 8 moles of aqueous 36 per cent formaldehyde solution were added to the mixture. The reaction mixture was heated to 68 C., the external source of heat removed and the temperature of the reaction controlled at about 68 C. by means of external cooling. After the heat of reaction had been dissipated, the mixture was stirred for about minutes and then cooled to ambient temperatures. The reaction mixture was diluted with 300 parts by volume of methanol and distilled. However, since the odor of formaldehyde still was prevalent an additional 300 parts by volume of methanol were added and the mixture allowed to stand for about 16 hours. Thereafter the mixture was distilled and a distillate amounting to 187 parts by weight (containing 50 per cent thiophene) was obtained. A heavy oily layer of about 86 parts by weight was separated from the aqueous still residue. The aqueous layer was neutralized with about 4 moles of aqueous per cent caustic soda, extracted with benzene and the extract distilled to remove the benzene. About 56.5 parts by weight of Z-thenylamine having a boiling point of 75 C., at a pressure of 5 millimeters of mercury, and a refractive index, a of 1.5636 were recovered. This yield is equivalent to 40 per cent of theory based upon the amount of thiophene reacted. In addition to the 2-thenylamine about 31 parts by weight of N-(Z-thenyl) formaldimine having a boiling point of 13'?" to 140 C., at a pressure of 3 millimeters of mercury, and a refractive index, n of 1.6019

The procedure described under Example II was repeated with some changes. Thus, about 4 moles of thiophene and about 4 moles of ammonium chloride were mixed and about 6 moles of aqueoib 36 per cent formaldehyde solution were added. The reaction mixture was heated to about 68 C., the external source of heat removed, and the reaction temperature maintained substantially constant for about 15 minutes by .external cooling. Agitation of the reaction mixture was continued until the reaction temperature dropped to 4050 C. Thereafter about 3 moles of unreacted thiophene were removed. Five hundred parts by volume of methanol were added and the mixture allowed to stand for about 16 hours. The methylal and methanol were removed by distillation; the distillation being discontinued when the pot temperature reached C. The still residue was neutralized with aqueous alkaline solution, the amines taken up in ether and rectified. The yield of 2-thenylamine was 64 parts by weight equivalent to about 58 per cent of theory based upon the reacted thiophene. In addition 17 parts by weight of a product having a boiling point of 116-120 C., at a pressure of 5 millimeters of mercury, and a refractive index, a of 1.5708 and 45 parts by weight of still residue were obtained.

EXAMPLE IV The procedure described under Example II was repeated with this exception, the reaction mixture was warmed to about 70 C. and refluxed at 70 C. for one hour after the initial heat of reacs. tiori had subsided. About 2.4 moles of 'u'nr'e'act'ed thiophene were removed and about'6'0 parts by weight of '2-thenylamine was recovered. In other words, a yield of 34 per cent based upon the reacted th-iophene was achieved instead of 58 per cent of theory. In addition, 13.5 parts by weight of a material boiling in the range, 90-' l25 0., at a pressure of millimeters mercury and having a refractive index, mu of 1.5576 together with about 93 parts by weight oi still residue were obtained. When the latter high boiling still residue was subjected to oxidation by alkaline permanganate in the conventional manner 2,5-thiophene-dicarboxylic acid having melting point of 358.5-359.5 C. was obtained.

EXAMPLE V The procedure described underExampleIII was followed using about moles of thiophene, about moles of methanol-free aqueous per cent formaldehyde solution and about 8 moles of ammonium. chloride. The temperature of the reaction was maintained at f-71 0., for 30 minutes by means of external cooling. Unreacted thiophene was removed and 1000 parts by volume of methanol used for the alcoholysis. Distillation of the residue of the extract from the aqueous layer of the still residue achieved the following results:

1 solidified at 210+.

Fractions 4 through 8 (both included) were redistilled with the following result'sr Table II St'll V I P 1 apor res- P v Y 31 E by 30 Fraction i\o. le ip (Pond-p sugxelnzin. Weight on 62 3.8 i 70 3. i 20 1.5593 90 2. 7 9 1. 5582 11 3 5 1.5506 123-124 2. 5 8 l. 5578 70-122 2. 3 7 153 135 2. l; 6. 5 1. 5670 170 147 1. 6 ll. 5 1. 5838 230 1. 6 l2 1. 5920 Investigation of these fractions established that fractions 1a and Za'are essentially 2-theny1amine. Fraction 4a was analyzed for nitrogenand sulfur with the following results: Nitrogen 7.77 per cent; sulfur 23.20 per cent. Treatment of a portion of fraction 4a with ph'enylisothiocyanate yielded a phenylthiourea. The purified phenylthiourea had a melting point of 100-101 C. It would appear from data presently available that the essential ingredient of fraction 4a is 6 For example, when oxidized in the conventional manner with alkaline permanganate 2,5-thiophene-dicarboxylic acid is formed. The phenylthiourea when analyzed yielded the following results: carbon 57.28 per cent; hydrogen 5.61 per cent; nitrogen 9.76 per cent; and sulfur 21.92 per cent. The composition calculated for the empirical formula C14H16N2OS2 is carbon 57.53 per cent; hydrogen 5.48 per cent; nitrogen'9.63 per cent; and sulfur 2182 per cent. -I'h'erefore'thestruc ture of the phenylthiourea is:

from which it follows that the essential ingredient of fraction dais EXAMPLE -VI About 10 moles of thiophene, about 1'0 moles-of paraformaldehyde and about 5 moles of ammo nium chloride were mixed. To the mixture about 100'parts by volume (95 parts by weight) of acetic acid were added and thereaction otherwise processed in the manner described under Example III. That isto say, the'mixture was heated to 66 C. to initiate the reaction. Thereafter the temperature was maintained b'y means of an ice-bath at 66-69 C. for twenty-five minutes. 'After the temperature fell, about 4. 5 moles of unreacted thiophene were recovered. After the removal of the thiophene, about 1000 parts by volume of methanol were added and the reaction mixture treated as described under Example III. Distil lation yielded 116.5 parts by weight of g-thenylamine (a yield 0121 per cent of theory based upon the thiophene reacted) and about 116.5 parts by weight of di-(2-thenyl)-amine having a, boiling point of 141-144 (3., at a pressure of '2 millimeters ofmercury, and a refractive index, 71,9 of 1.5968. This represents a yield of 22 per cent of theory based upon the amount of thiophene reacted. A still residue of 216 parts by weight was also obtained. The composition and characteristics'of the still residue will be discussed hereinafter.

EXAMPLE VII The procedure described under Example "VI was repeated with great exactitude except that the reaction temperature was maintained by external cooling between 65 and 67 0. About 4.75 moles of unreactedthiophene werer-ecovered. The yield of Z-thenylamine was about 20 per cent of theory and the yield of di-(Z-thenyl amine about 32 percent-of theory.

EXAMPLE VIII About 5 moles of thiophene and about '10 moles of 'paraformaldehyde were mixed. About 5 moles of ammonium chloride and about one mole of water were added to the mixture. The reaction mixture was warmed to 65 C. and the temperature of the reaction mixture held at-67 C. by means of an ice-bath for thirty minutes. No thiophene could be recovered. About 1000 parts by volume of methanol were added and the mixture processed as described hereinbeiore. Ayild of about 22 "percent of Z thenyIamin'e Was obs.

a t'aine'd. However, a fraction having a boiling range of 118 to 160 C. at a pressure of 4 millimeters of mercury contained only a trace of di-(Z-thenyl) amine. This higher boiling fraction will be discussed hereinafter.

A comparison of the results obtained in Examples VII and VIII establishes that acetic acid or an acid having an ionization constant of about 1 10 to about l must be present if di-(Z-thenyDamine is to be obtained in significant yields.

EXAMPLE IX About 4 moles of thiophene and about 4 moles of ammonium chloride were mixed. About 8 moles of aqueous 36 per cent formaldehyde solution and about 100 parts by volume of acetic acid were added to the reaction mixture. The temperature of the reaction was maintained as in Example III. About 1.8 moles of unreacted thiophene were recovered. A yield of 36 per cent of theory of 2-thenylarnine was obtained as compared with a yield of 58 per cent of theory in Example III.

In addition about 19 parts by weight of a material having a boiling range of 123-133 C. at a pressure of 2.2 millimeters of mercury were recovered. This material contained little, if any, di(2-thenyl)amines and corresponds in various characteristics to the distillate obtained in Example III.

Thus, it would appear, that the action of acetic acid or acids having an ionization constant of about 2 10- with paraformaldehyde to increase the yield of di-(Z-thenyl) amine is specific.

EXAIVEPLE X About 20 moles of formaldehyde in the form of an aqueous 36 per cent solution thereof and about 10 moles of ammonium chloride were added to about 5 moles of 3-methylthiophene. Thereafter the temperature of the reaction mixture rose to about 50 C. and was maintained within the interval C. to C. by means of external cooling for about forty-five minutes. At this time substantially no 3-methylthiophene remained in the reaction mixture. Thereafter about 33 moles of methanol were added and the mixture allowed to stand at room temperature for about sixteen hours. recovered as described hereinbefore. A 31 per cent yield of 3-methyl-2-thenylamine having a boiling point of 78 C., at a pressure of 4.2 millimeters of mercury and a refractive index, 11,

of 1.5772 was obtained. The product was oxidized in the conventional manner with alkaline permanganate to 3-methyl-2-thiophenecarboxylic acid having a melting point of 1461i7 C. A melting point determination of this acid when mixed with an authentic sample of 3-methyl-2- thiophenecarboxylic acid showed no depression.

EXAMPLE XI About 20 moles of formaldehyde in the form of an aqueous 36 per cent solution thereof and about 10 moles of ammonium chloride were added to about 5 moles of thiophene. The well-stirred mixture was heated to about 60 C., and the source of external. heat removed. Thereafter the temperature of the reaction was maintained at about 64 to about 65 0., for about forty-five minutes. (It is important to maintain the reaction temperature at about C. since the yield decreases if the reaction temperature is allowed to rise to about 68 C. or above.) The reaction mix- The alcohol was distilled and the amine I ture was then stirred until the temperature of the reaction mixture fell to ambient temperature and about 50 moles of methanol were added. (The amount of alcohol is not critical it being an excess of the stoichiometric amount.) The alcoholysis was allowed to proceed for about sixteen hours after which the reaction mixture was treated as described hereinbefore to recover the thenylamines.

After removal of the alcohol the product was distilled and fractions obtained as indicated in the following table.

Table III Pressure mm. Parts by Cut B. P., C. Hg m): Weight 3. 5 62 3. 5 1. 5628 111 65 4. 0 1. 5630 107 66 4. 0 1. 5626 21 66 4. 0 1. 5624 10 67 4. O 1. 51320 6 100 4. 0 1.5628 7 132 4. l. 5670 14 135 4.0 1.5750 22 Residue 200 The principal constituent of cuts -5 (both inclusive) is 2-thenylamine. Cuts 6-8 (both inclusive) contain some di-(2-thcnyl)amine EXAMPLE XII About 4 moles of formaldehyde (as an aqueous 36 per cent solution thereof) and about 2 moles of ammonium chloride were added to about 2 moles of Z-methylthiophene. The temperature of the reaction mixture was maintained at about 35-40 C. for about four hours by means of external cooling. The di-(5-methyl-2-thenyD- amine hydrochloride crystallized and was separated in 57 per cent yield. When recrystallized from water the di-(5-methyl-2-thenyl) amine hydrochloride had a melting point of 216 to 217 C.

About 8 moles of methanol (an excess) was added to the filtrate from the crystals of (ii-(5- methyl-2-thenyl)amine hydrochloride and the reaction mixture stirred for about sixteen hours. The methanol and methylal were distilled at a pot temperature of 90 C. The residue was cooled to ambient temperatures, neutralized with an aqueous 40 per cent sodium hydroxide solution, cooled to ambient temperatures again, and the amine extracted from the neutralized aqueous solution with ether. After distillation of the ether the 5-methyl-2-thenylamine in 16 per cent yield distilled at 6758 (3., at a pressure of 3 milli meters of mercury and had a refractive index, 11. of 1.5514. The phenylthiourea thereof and the hydrochloride had melting points of 133-134 C. and 196197 C., respectively.

EXAMPLE XIII About 2 moles of paraformaldehyde and about 1 mole of ammonium chloride together with about 0.34 mole of acetic acid were added to about 1 mole of 2-chlorothiophene. The mixture was agitated at --75 C. for about two hours, cooled to ambient temperatures and the di-(5-chloro-2- thenyDamine hydrochloride in the amount of about 26 parts by weight filtered off. This hydrochloride had a melting point of 20242 C. From the filtrate about 50 parts by weight of unreacted 2-chlorothiophene were recovered. The

filtrate from the hydrochloride crystals was then treated as described in Example XII. Upon distillation 5-ch1oro-2-thenylamine-having a boiling point of 71 C., at a pressure of 2 millimeters of mercury and a refractive index, n of 1.5630 was obtained in 18 per cent yield. A phenythiourea of this amine melted at 1l9.5-l20 C. .5

EXAMPLE XIV About 1 mole of tertiary-butylthiophene, about 2 moles of formaldehyde (aqueous 36 per cent solution) and about 1 mole of ammonium chloride were mixed and held at a temperature of about 7080 C. for about three hours. An excess of methanol was added and the solution agitated for about sixteen hours. methanol and the methylal together with about 0.5 mole of unreacted tertiary-butylthiophene were removed by distillation. The residue from the distillation was neutralized and extracted with ethyl ether. the extract and the residue of the extract distilled to yield the fractions tabulated hereinafter.

Table IV Pressure arts by mm. of Hg Weight 75 2. 1.5038 5 75 2. 5 1. 5040 2 78 l. 5 l. 5048 13 85 l. 5 1. 5110 9 5 125 l. 5 l, 5230 5 Residue 24 Cut 3 yielded a phenylthiourea having a melting as acetic acid, having an ionization constant of 1 about 1 to about l X 10*, separating the unreacted compound capable of undergoing the Mannich reaction, adding an alcohol and recovering primary and secondary amines corresponding respectively to the formulae RCHzNI-Iz and (RCH2)2NH where R has the same significance as given hereinbefore.

We claim:

1. A method of preparing a thenylamine which comprises treat ng a thenylformaldimine with alcohol. in acid solution.

2. A method of preparing a thenyalmine which The excess unreacted The ethyl ether was removed from adding an alcohoL'and recovering Z-thenylamine.

5. A method of preparing substituted 2-theny1- amine which comprises reacting a thiophene derivative having at least one unsubstituted" alpha position, ammonium halide and formaldehyde at a temperature not greater than about 0., recovering unreacted thiophene derivative, adding an alcohol and recovering substituted 2- thenylamine.

6. A method for preparing Z-thenylamine and the secondary amine di-(2-thenyl)amine, which comprises reacting thiophene, ammonium halide and paraformaldehyde in the presence of an acid having an ionization constant of about 1X10- to about 1x10- separating unreacted thiophene, adding an alcohol, and recovering Z-thenylamine and di- (Z-thenyl) amine.

7. As a new composition of matter, E-hydroxymethyl-Z-thenyl, N-methyl amine having a composition corresponding to the formula boiling at 123-124 C., at a pressure of 2.3 millimeters of mercury, forming a phenylthiourea having a melting point of -101 C. and containing about 57.53 per cent carbon, about 5.48 per cent hydrogen, about 9.63 per cent nitrogen, about 21.92 per cent sulfur and about 5.44 per cent oxygen.

8. As a new composition of matter, di-(5- methyl-Z-thenyl) amine having in the form of the hydrochloride a melting point of about 216 to 217 C.

9. As a new composition of matter, di-(5- chloro-Z-thenyl) amine having in the form of the hydrochloride a melting point of about 240- 242 C.

10. As a new composition of matter, 5-chloro- 2thenylamine having a boiling point of 71 C.

, at a pressure of 2 millimeters of mercury, a recomprises reacting a thenylformaldimine and fractive index, n of 1.5630 and yielding a phenylthiourea having a melting point of 119.5"- C.

11. As a new composition of matter, 3-methyl- Z-thenylamine having a boiling point of 78 C., at a pressure of 4.2 millimeters of mercury and a refractive index, 12 of 1.5572 and yielding a phenylthiourea having a melting point of 137- 138 C.

12. A method for preparing thenylamines, which comprises reacting a thiophenic reactant comprising a, thiophene having at least one unsubstituted alpha position, ammonium halide and paraformaldehyde in the presence of an acid having an ionization constant of about 1 10- to about 1X10- separating the unreacted portion of said thiophenic reactant, adding an alcohol and recovering primary and secondary thenylamines.

13. A method for preparing thenylamines, which comprises reacting a thiophenic reactant comprising a thiophene having at least one unsubstituted alpha position, ammonium halide and paraformaldehyde in the presence of solvent quantities of acetic acid, separating the unreacted portion of said thiophenic reactant, adding an alcohol, and recovering primary and secondary thenylamines.

14. As a new composition of matter, a thenylamine having a composition corresponding to the formula I?! RNH wherein R is selected from the group consisting 9f yl, -hydr0X'ymethyl-2-thenyl, 5-meth- 11 yl-2-theny1, 5-ch1oro-2-thenyl and 3-methyl-2- thenyl, R is selected from the group consisting of hydrogen, methyl, 2-theny1 and when one of R and R. is 2-theny1 the other is 2-thenyl.

HOWARD D. HARTOUGH. SEYMOUR L. MEISEL.

'12 REFERENCES CITED The following references are of record in the file of this patent:

Organic Reactions, v01. 1, 303 if, Wiley, N. Y., 1942.

J. Am. Chem. 800., '70, 4013-4019 (1948).

Certificate of Correction Patent No. 2,533,798 December 12, 1950 HOWARD D. HARTOUGI-I ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows:

Column 1, line 48, left-hand portion of Equation 1, for RI-I read RH line 52, right-hand portion of Equation 2, for CH (OR) read CH 0R1; line 54, for H read I] ,7 column 2, line 47, right-hand portion Equation 3, for CH (OR) read C H (0R) line 56, right-hand portion of Equation 5, for GH (OR) read UH (OR) and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 29th day of May, A. D. 1951.

THOMAS F. MURPHY,

Assistant Oommz'ssz'oner of Patents. 

14. AS A NEW COMPOSITION OF MATTER, A THENYLAMINE HAVING A COMPOSITION CORRESPONDING TO THE FORMULA 